The long-term goal of this laboratory is to understand the molecular mechanisms underlying the development and function of synapses. A number of model systems are used in our studies, including Xenopus nerve-muscle cultures, dissociated cultures of mammalian brain neurons, brain slices and knockout mice. Our recent efforts focus on the function of neurotrophic factors in synapse development and plasticity. We have discovered that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal long-term potentiation (LTP), a cellular model for learning and memory. We have shown that the BDNF effect on LTP was due to an attenuation of the synaptic fatigue induced by high frequency, tetanic stimulation, and was confined only to the tetanized synapses. Several lines of evidence suggest that BDNF promotes LTP and high frequency synaptic transmission through a presynaptic mechanism. These results indicate that BDNF preferentially enhances highly active synapses, and therefore provide a basis for the involvement of neurotrophins in the Hebbian model of synaptic plasticity. To test the role of neurotrophins in the Hebbian model more rigorously, we used the Xenopus neuromuscular synapse as a model system. The expression of neurotrophin-3 (NT-3) in the postsynaptic muscle cells was found to be enhanced by depolarization, elicited either by depolarizing agents, repetitive electric stimulation, or the neurotransmitter ACh. We also showed that the postsynaptically-derived NT-3 potentiates ACh release from presynaptic terminals of motoneurons. Thus, at least at the neuromuscular synapses, the postsynaptically-derived neurotrophin NT-3 indeed serve as a retrograde messenger for activity-dependent synaptic strengthening. Finally, we have initiated a project studying the function of the members of glial derived neurotrophic factor (GDNF) family of neurotrophic factors.